Vancomycin is a small glycopeptide and is considered an antibiotic of “last resort” for fighting infections by Staphylococcus aureus and Clostridium difficile. However, at the beginning of 1987, hospitals began reporting vancomycin resistant strains of enterococci. Vancomycin acts by interfering with the biosynthesis of the bacterial cell wall. It binds to the peptide substrates [Ala-Glu-Lys-Ala-Ala] and prevents it from cross-linking carbohydrates in the cell wall. Resistant bacteria, however, overcome vancomycin's effect by synthesizing [Ala-Glu-Lys-Ala-lactate]. Vancomycin does not bind well to this moiety; and therefore the bacterial cell wall is synthesized.
The emergence of vancomycin-resistant Enterococci and Staphylococci (VRE/VRS) clinical isolates in conjunction with the demonstrated antiviral properties of certain glycopeptides, continues to promote the search for efficient routes of rapid glycopeptide diversification.
The rapid diversification of glycopeptides via glycorandomization reveals significantly diverse substitutions are tolerated and suggests there may be a synergistic benefit to the construction of mechanistically—related natural product core scaffold fusions. Glycorandomization is a chemoenzymatic process in which scaffold of a natural compound is altered through alteration of its sugar moieties. Since sugar groups help determine biological activity in large number of pharmaceutically interesting compounds, glycorandomization is an important process in developing new therapeutic compounds.
Toward this goal, recent research has revealed that alterations to the vancomycin's L-vancosaminyl-1,2-D-glucosyl disaccharide attachment, via chemical or chemoenzymatic impacts upon both the molecular target and organism specificity.
However, the need exists for yet newer molecules and architecture, especially using chemoenzymatic approaches to diversify complex natural products that may be capable of countering the effects of vancomycin-resistant Enterococci and Staphylococci.